Millions of persons in the world continue to die of diseases that can be treated, prevented or even inhibited. Inadequate or even non-existing treatments to infectious and parasitic diseases are victimizing an elevated number or persons, especially in countries in development. Thousands of lives are lost or severely damaged due to these diseases that impact the social well-being and exclude an important parcel of individuals from their social and productivity activities.
Neglected diseases is the classification attributed to diseases that do not present a satisfactory treatment, do not create interest in pharmaceutical industries and, besides that, government funding is insufficient to fight these kinds of diseases. Tuberculosis, HIV/Aids and malaria are examples of neglected diseases, because although they affect individuals from developed countries, they mainly afflict populations of countries in development and they create only a peripheral interest from the pharmaceutical market. The lack of investment from pharmaceutical industries in the development of new drugs for certain diseases is directly connected to the low capacity of purchase of populations of countries in development.
The lack of interest, on the part of the pharmaceutical industries, for neglected diseases is so severe that within the period of 25 years, from 1975 to 1999, from the 1.393 new drugs licensed, only 15 pertain to this class, 13 being for tropical diseases and 2 for tuberculosis.
The urgency on the discovery of new drugs for neglected and extremely neglected diseases has motivated survey and development in several countries, including Brazil.
Tuberculosis (TB) is an infectious disease transmitted through the airway by a bacterium called Mycobacterium tuberculosis, also known as Koch bacillus in honor of the scientist Robert Koch, who isolated it in 1882. There are several forms of tuberculosis (lung, meningeal, milliary, bone, renal, cutaneous, genital, etc), however, the most frequent form and the most contagious one is the pulmonary. A patient with pulmonary tuberculosis, if not treated, can infect from 10 to 15 persons in a year.
From reports of the presence of fragments of the bacillus in Egyptian mummies in 2400 B.C., tuberculosis presently infects approximately one third of the world population and it is the main cause of death in countries in development. We estimate that 70% of the population in destitute countries is infected by the Koch bacillus, and every year, 7.5 million new cases are reported and 2.8 million of deaths. The high rate of incidence of the disease in these is closely connected to the precarious life conditions of the population. In India, for instance, which holds 15% of global populations, approximately 30% of the population is infected by the M. tuberculosis and tuberculosis kills 14 times more people than all tropical diseases.
Brazil, according to the World Health Organization (WHO), presents the most elevated number of cases of tuberculosis in Latin America, that is, 62 new cases per 100.000 inhabitants, presently being the fourteenth among the 23 countries responsible for 80% of the total cases of tuberculosis in the world. Sources from Health Ministry estimate a prevalence of 58/100.000 cases/inhabitants, within the country, with approximately 111 mil new cases/year, and Rio de Janeiro being the state with higher incidence and occurrence of approximately e 6.0 mil deaths/year from the disease.
HIV infection is one of the most significant risk factors known for tuberculosis infection.
It is estimated that one third of 42 million individuals infected by HIV are co-infected by M. tuberculosis and most of the persons infected by HIV develop TB as their first AIDS sign. Since HIV progressively destroys the immune system, there is a greater chance that virus infected persons develop tuberculosis. This relation among epidemics is especially concentrated in destitute countries. In Sub-Saharian Africa, for instance, approximately 50% of persons with HIV develop TB and one in three dies in consequence of the disease.
On the other hand, the increased number of multidrug-resistant tuberculosis (TBMR) has caused great concern, because it contributes to increase the ration of deaths by TB, and being frequently associated to HIV infection.
Tuberculosis is a serious disease, but it is curable in practically 100% of new cases, as long as modern chemotherapy principles are followed, the adequate association of drugs and their regular use, for sufficient time are the necessary means to avoid bacterial resistance and persistence.
Chemotherapy for tuberculosis started during the 40's when the studies about tuberculostatic agents resulted in the discovery of several active substances face M. tuberculosis (Tripathi, R. P.; Tewari, N.; Dwivedi, N.; Tiwari, V. K.; “Fighting Tuberculosis: An Old Disease with New Challenges”; Med. Res. Rev., 2005, 25, 1, 93-131). The presence of multi-resistant lineages reflects deficiencies in the control of TB, thus hindering treatment and prevention of the disease, causing its propagation (Rossetti, M. L. R.; Valim, A. R. M.; Silva, M. S. N.; Rodrigues, V. S.; “Tuberculosis resistente: revisão molecular”; Rev. Saúde Pública, 2002, 36, 525-32).
The first drug really active against tuberculosis, discovered by Selman Walksman, in 1943, was streptomycin (SM) (Formula I where R═CHO) an aminoglycoside antibiotic insulated from the Streptomyces griseus bacterium. However, SM administered in higher doses can affect the central and peripheral nervous systems. Different synthetic by products from streptomycin have been synthesized and have shown to be active as tuberculostatic, such as, for example, dihydrostreptomycin (Formula I where R═CH2OH), which although demonstrates to be active can cause irreversible damage to the hearing system.

The p-amino-salicylic acid (PAS) (Formula II), first reported in 1946, presents great and selective activity against M. tuberculosis. It was used combined to SM, but presently, according to WHO, its use is directed to the multidrug-resistant tuberculosis treatment.

With progress of researches, new drugs have been introduced in therapy. Some of them are still used in treating tuberculosis, such isoniazide (INH) (Formula III), firstly used in 1952, and rifampicin (RMP) (Formula IV), used as of 1967. These medicaments are still the basis of modern chemotherapy in treating the disease.

INH (Formula III) is active orally and besides exhibiting a bacteriostatic action against the bacillus, it is highly active against the M. avium complex. Its minimum inhibitory concentration (MIC) is very low (0.02-0.06 μg/mL) fact that contributes to its efficacy.
On the other hand, rifampicin (Formula IV, which is part of a semi-synthetic antibiotics group derived from rifamicin B, insulated from Streptomyces mediterrani, is extremely effective against M. tuberculosis, with a MIC of 0.1 μg/mL to 1.0 μg/mL, and it presents a quick bactericide action in the elimination of persistent bacteria.
Due to its efficacy and ease administration, rifampicin (Formula IV) is the drug chosen to treat patients co-infected by TB/HIV. However, rifampicin, as other by products of this class, presents a significant pharmaceutical interaction with several of the anti-retroviral, especially with protease inhibitors that have their concentration decreased by the inducing action of rifampicin.
Several compounds similar to INH have been synthesized and some have shown activity against M. tuberculosis H37Rv. Among them ethionamide (Formula V) and a pyrazinamide (PZA) (Formula VI), which are also used in TB chemotherapy.

Other significant drug used in treating tuberculosis, since 1968, is ethambutol (EMB) (Figure VII) which is active against many variables of Mycobacterium. EMB is a synthetic amino alcohol, firstly synthesized in 1960, with enantiomer as its stereo specific activity (Figure VII) with S,S configuration is the isomer that shows a tuberculostatic action, as the enantiomer R,R presents an undesirable action, since it causes blindness.

Drugs used in the tuberculosis can be classified as first line and second line drugs. First line drugs are part of the TB primary treatment plan and consist of the four medications previously mentioned isoniazide, rifampicin, pyrazinamide and ethambutol. The adequate treatment of patients with combinations of these agents during long periods (six to nine months) leads to cure in 95% of TB cases.
However, in cases with monotherapy, inadequate prescription, incorrect use of the primary plan by the patient or even intolerance to first line drugs can lead to failure in therapy and development of the M. tuberculosis strains resistant to one or more drugs. In this case, second line drugs are used.
Along with streptomycin (SM), p-amino salicylic acid and ethionamide, drugs used in the second chemotherapy plan are: Thiacetazone, D-cycloserine, clofazimine, terizidone, kanamycin and amicacin.

A significant class of antibiotics, fluoroquinolones, has been used in pulmonary, extrapulmonary and disseminated tuberculosis. These compounds were approved by WHO as second line agents to TBMR treatment and are employed in cases of resistance or intolerance to first line drugs.
Clinical studies have shown that during the first 48 hours of pulmonary tuberculosis ciprofloxacin and ofloxacin have demonstrated to be less potent than isoniazide. However, a gatifloxacin and moxifloxacin have shown a greater activity in relation to INH. A fact that should be mentioned is the non-existence of toxicity in ten patients submitted to six months therapy with moxifloxacin, isoniazide and rifampicin. Due to the high activity of the fluoroquinones as bactericides, several clinical studies are being made in order to make them first line drugs.

Leishmaniasis depicts a complex of diseases with a significant clinical and epidemiological diversity. Caused by approximately 20 species of protozoa of the Leishmania gender, it is transmitted to men by the sting of the female mosquito of the Phebotomine species in Europe and of the Lutzomyia species in South and Central America.
The diseases present two clinical forms: integumental leishmaniasis and visceral leishmaniasis. The Cutaneous Leishmaniasis (LC) is the most common of the manifestations and it is characterized by ulcerative nodular lesions. The onset of lesions appears where the vector insect stung, thus being more frequent in body areas exposed, for instance, limbs and face. The incubation period between the sting and the onset of the lesion can vary from a few weeks to months. However, the cutaneous leishmaniasis disseminated (LCD) is characterized by multiple and small lesions, with or without central ulceration, sometimes with an acneiform aspect. The diffuse form is a rare form of the disease detected in some of the Brazilian states, such as Maranhao, Para, Bahia and Mato Grosso.
The drugs presently recommended for the treatment of leishmaniasis (Croft, S. L.; Coombs, G. H.; “Leishmaniasis—current chemotherapy and recent advances in the search for novel drugs” Trends Parasit., 2003, 19, 502-508) are the pentavalent—the sodium stibogluconate (Pentostam®), the meglumine antimoniate (Glucantime®), the pentamidine and the amphotericin B and its three lipidic formulations—a liposomal amphotericin B, colloidal dispersion amphotericin B and a lipidic complex amphotericin B. Pentamidine was introduced in 1952 in therapy and even today it used as a third choice drug. Its use as a leishmanicide agent is restricted due to its high toxicity that can cause adverse effects such as nausea, vomiting, headache, hypoglycemia and sudden death.
Due to increased cases of leishmaniasis and to long and inadequate treatments with toxic drugs that are hard to be administered, the discovery of new leishmanicide agents has become mandatory.
There is not, in all the extension of chemical, pharmacological and medical literature, either in magazines, journals, encyclopedias, books or patents, a quotation for the use of the 1,2,3-triazoles and imidazole as tuberculostatic and leishmanicide agents, of potential use for the treatment of tuberculosis and leishmaniasis.